The conformational changes of both partners of a ligand-protein complex, the small-molecule ligand its the protein binding site (in many cases the catalytically active site of an enzyme) are a central aspect many drug actions, as well as a crucial challenge in computational approaches to drug design. In one of the earliest publications in the this field, we (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=8581425&ordinalpos=47&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum") showed for a small set of ligands occurring both in the Protein Data Bank (PDB) and the Cambridge Structural Database (CSD) that flexible compounds are not usually bound to a protein in their global vacuum energy conformation, and oftentime not even in any local vacuum energy conformation. While this study used the largest set of data and best methodology available at that time, both the number of structures in either experimental database and the software and hardware resource available have since grown exponentially. We are thus revisiting this important topic with an analysis of orders of magnitudes more structures, and computations performed at a high level of computational quantum-chemical theory. Among other milestones achieved so far in this project, we have extracted all occurrences of small-molecule ligands recently made available in PDB's (http://ligand-expo.rcsb.org/) LigandExpo. As of May 2008, this is a set of over 350,000 distinct sets of 3D coordinates. We have added extensive annotation coming from several different sources. Using these annotations in a chain of filters, we have generated "high-quality" subsets of ligand structures of high quality and reliability numbering from just about one thousand to about 5,000 occurrences depending on the stringency applied. We have begun high-level quantum-chemical calculations of conformational energies for these high-quality ligand sets. As of the time of this writing, on the order of 800 ligand occurrences have been submitted to vacuum energy calculations, partly on our own Linux cluster, partly on the (http://biowulf.nih.gov/) Biowulf cluster of the CIT, NIH. Most jobs have finished, but some are still running. Up to a thousand CPUs are used simultaneously in this computationally massive project, with individual jobs taking from a few hours to several weeks of CPU-time. First survey of the incoming results indicate that the possibility for high conformational energies are fully confirmed by these quantum-chemical calculations.